Deterioration of the intervertebral discs, located between the vertebrae, is common in older vertebrates. Age-related changes in the intervertebral discs are thought to cause most cases of back pain. In the US alone, >50 billion dollars per year are spent on the treatment of back pain, and there is presently no cure for a damaged and/or degenerating intervertebral disc. A cure for back pain caused by disc disease would be a monumentally life-altering medical advance for millions of Americans. In spite of the essential role the intervertebral discs play in everyday life and the huge financial burden damage to these structures places on our health care system. There is very little known about the molecular pathways acting in this tissue. We propose to perform an innovative genome-wide, unbiased genetic screen in mice to identify genes that are responsible for forming the intervertebral disc. A number of successful genome-wide genetic screens have previously been performed in mice. None of these screens were designed to uncover mutations affecting the intervertebral discs, identification of which would have required extensive processing of the vertebral column. To overcome this labor-intensive hurdle, we propose to perform our screen in a strain of mice in which the intervertebral discs express eYFP, and therefore glow. This will allow my research team to quickly determine if discs have been lost (by absence of eYFP) or have lost their structural integrity (eYFP present in an abnormal pattern). Without the use of this novel strategy it would be extremely difficult to identify mutations that affect the discs. Since te screen will be performed in postnatal mice, my laboratory will be able to identify genes that, upon mutation, are viable and affect maintenance or formation of the discs. The lack of molecular targets for the development of protein- or gene-based therapies to halt or heal discs that have been damaged or are degenerating has greatly limited treatment options for millions of patients suffering from these conditions. The proposed innovative screen is risky but has the potential to generate more knowledge about the molecular components involved in forming and maintaining disc structure than the entire field has generated in the last 50 years.